Using Flow To Outpace Fast Proton Transfer in an Organometallic Reaction for the Manufacture of Verubecestat (MK-8931)

We report that an organolithium addition to a chiral ketimine, which because of competitive proton transfer proceeds with only modest yield in batch, can be significantly improved in flow. The transformation was discovered to be highly mixing-sensitive but remarkably temperature-independent in flow, enabling the continuous process to be performed under noncryogenic conditions. Experiments at the kilogram scale provided robust operating conditions that are amenable to implementing this chemistry for the manufacture of verubecestat (MK-8931), a drug candidate for the treatment of Alzheimer’s disease.